Bacteria have developed little or no resistance to antimicrobial peptides (AMPs) as opposed to antibiotics where the resistance is well established and is a major health concern worldwide killing 100 000’s of people each year. Arenicin-3 part of the Arenicins family, isolated from the marina polychaeta lugworm Arenicola marina, is composed of 21 amino acids and 2 disulfide bonds. Arenicin-3 and its analogs exhibit potent antimicrobial activity in vitro against a broad range of multi-resistant pathogenic Gram-negative bacteria, including polymyxin resistant P. aeruginosa, K. pneumoniae and A. baumannii. The peptides also demonstrate in vivo activity in urinary tract infection and pneumonia mouse models. However, despite being potent, Arenicin-3 displays high toxicity against mammalian cells and therefore results in inapplicability as drug candidate. This study characterizes the structural features of Arenicin-3 and its analogs creating therapeutically valuable properties.
The 3D NMR structures of Arenicin-3 and its analogs demonstrate that a slight twist modification as well as a rearrangement of one amino acid of the β-hairpin increases the amphipathicity of the molecule and therefore modify its toxicity. Surface Plasmon Resonance demonstrates the binding affinity toward (palmytoyloleoylphosphatidylglycerol) POPG as opposed to (palmitoyloleoylphosphatidylcholine) POPC lipid bilayer confirming the selectivity of the molecules for the bacteria cells. Circular dichroism spectra emphasise again that selectivity for bacteria cell showing that the secondary structure of the arenicin-3 and analog were similar in aqueous solution and in presence of POPC vesicles but significantly different in the presence of POPG vesicles. Those results are the preliminary basis of the understanding of the mechanism of action and the start of a systematic design of concept to create other therapeutical AMPs.